Changes in dopaminergic transmission in mesolimbic and mesocortical pathways have been implicated in certain psychiatric disorders and in the mechanism of action of antipsychotic drugs such as haloperidol. The functional activity of these dopaminergic neurons is most likely dependent on their pre- and/or postsynaptic relations with neurons containing other transmitters or modulators. The goals of the presently funded and proposed studies are to determine: (1) the anatomical substrate for functional interactions between the dopaminergic neurons and neurons containing gamma aminobutyric acid (GABA), substance P, or neurotensin, and (2) the time-dependent alterations In the ultrastructural features of neurons containing one or more of the identified transmitters following chronic treatment with neuroleptic drugs. These goals will be achieved by examining the single or dual immunocytochemical localization of tyrosine hydroxylase, an enzyme involved in catecholamine synthesis, GABA, substance P and neurotensin in the nucleus accumbens (Study 1), medial prefrontal cortex (Study 11), and ventral tegmental area (Study 111) of normal adult rats and rats receiving long-term (2-4 mo) treatment with haloperidol. In addition, the anatomical substrate for functional relationships between dopaminergic axons or GABAergic neurons and other afferents from the hippocampal formation or amygdaloid nuclei will be examined in the nucleus accumbens by combining immunoautoradiographic labeling with anterograde degeneration or transport of conjugated horseradish peroxidase. The results will be quantitatively examined by computer-assisted densitometry of immunoautoradiographs and morphometric analysis of peroxidase- labeled profiles by electron microscopy. Further characterization of normal synaptic relationships and morphological changes observed following chronic administration of a neuroleptic drug is relevant to the understanding of the etiology and the implementation of better treatments for psychiatric disorders which Involve mesolimbic and cortical dopaminergic neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH040342-13
Application #
2430919
Study Section
Special Emphasis Panel (NSS)
Project Start
1985-09-01
Project End
1998-08-31
Budget Start
1997-06-01
Budget End
1998-08-31
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Glass, Michael J; Chan, June; Pickel, Virginia M (2017) Ultrastructural characterization of tumor necrosis factor alpha receptor type 1 distribution in the hypothalamic paraventricular nucleus of the mouse. Neuroscience 352:262-272
Gasser, Paul J; Hurley, Matthew M; Chan, June et al. (2017) Organic cation transporter 3 (OCT3) is localized to intracellular and surface membranes in select glial and neuronal cells within the basolateral amygdaloid complex of both rats and mice. Brain Struct Funct 222:1913-1928
Garzón, Miguel; Pickel, Virginia M (2016) Electron microscopic localization of M2-muscarinic receptors in cholinergic and noncholinergic neurons of the laterodorsal tegmental and pedunculopontine nuclei of the rat mesopontine tegmentum. J Comp Neurol 524:3084-103
Glass, Michael J; Wang, Gang; Coleman, Christal G et al. (2015) NMDA Receptor Plasticity in the Hypothalamic Paraventricular Nucleus Contributes to the Elevated Blood Pressure Produced by Angiotensin II. J Neurosci 35:9558-67
Gan, J O; Bowline, E; Lourenco, F S et al. (2014) Adolescent social isolation enhances the plasmalemmal density of NMDA NR1 subunits in dendritic spines of principal neurons in the basolateral amygdala of adult mice. Neuroscience 258:174-83
Fitzgerald, M L; Mackie, K; Pickel, V M (2013) The impact of adolescent social isolation on dopamine D2 and cannabinoid CB1 receptors in the adult rat prefrontal cortex. Neuroscience 235:40-50
Garzón, Miguel; Pickel, Virginia M (2013) Somatodendritic targeting of M5 muscarinic receptor in the rat ventral tegmental area: implications for mesolimbic dopamine transmission. J Comp Neurol 521:2927-46
Garzón, M; Duffy, A M; Chan, J et al. (2013) Dopamine D? and acetylcholine ?7 nicotinic receptors have subcellular distributions favoring mediation of convergent signaling in the mouse ventral tegmental area. Neuroscience 252:126-43
Glass, Michael J; Robinson, Danielle C; Waters, Elizabeth et al. (2013) Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior. Synapse 67:265-79
Fitzgerald, Megan L; Shobin, Eli; Pickel, Virginia M (2012) Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuropsychopharmacol Biol Psychiatry 38:21-9

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